CN103703014A - Process for the production of estetrol intermediates - Google Patents

Process for the production of estetrol intermediates Download PDF

Info

Publication number
CN103703014A
CN103703014A CN201280026162.1A CN201280026162A CN103703014A CN 103703014 A CN103703014 A CN 103703014A CN 201280026162 A CN201280026162 A CN 201280026162A CN 103703014 A CN103703014 A CN 103703014A
Authority
CN
China
Prior art keywords
compound
group
alkyl
formula
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201280026162.1A
Other languages
Chinese (zh)
Inventor
让-克洛德·帕斯卡尔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Estetra SRL
Original Assignee
Estetra SRL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Estetra SRL filed Critical Estetra SRL
Priority to CN201710354709.5A priority Critical patent/CN107266514A/en
Publication of CN103703014A publication Critical patent/CN103703014A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
    • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a process for the preparation of a compound of formula (I) the process comprising the steps of : a) reacting a compound of formula (II), with an acylating or a silylating agent to produce a compound of formula (III), wherein P1 and P2 are each independently a protecting group selected from R2-Si-R3R4, or R1CO-, wherein R1 is a group selected from C1-6alkyl or C3-6cycloalkyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1-4alkyl; R2, R3 and R4 are each independently a group selected from C1-6alkyl or phenyl, each group being optionally substituted by one or more substituents independently selected from fluoro or C1-4alkyl; b) reacting the compound of formula (III) in the presence of palladium acetate or a derivative thereof to produce compound of formula (IV); and c) reacting the compound of formula (IV) with a reducing agent to produce compound of formula (I).

Description

Method for generation of oestetrol intermediate
Technical field
The present invention relates to the novel method for the synthesis of the key intermediate in synthetic oestetrol.
Background technology
Estrogen substance is generally used for the method for Hormone Replacement Therapy (hormone replacement therapy, HRT) and the method for female contraception.Oestetrol is the biogenic estrogen being produced by tire liver (fetal liver) endogenous at people's pregnancy duration.In the recent period, find that oestetrol is effective as estrogen substance for HRT.The field of other important application of oestetrol is: prevention and treatment, sexual desire enhancing, skin care and the wound healing for the treatment of, breast tumor and the colon tumor of contraception, autoimmune disease.
Synthesizing of oestetrol and derivative thereof is known in the art.Verhaar M.T; Deng (WO2004/041839), described from 3-A-oxygen base-female 1,3,5 (10), the initial method of preparing oestetrol of 15-tetraene-17-ketone, wherein A is C 1-C 5alkyl or C 7-C 12benzylic group (benzylic group).In the document; 3-A-oxygen base-female 1; 3; 5 (10); 15-tetraene-17-alcohol is prepared through 6 steps from oestrone; wherein A is benzyl, and these steps comprise the group by benzyl protection 3-OH, uses afterwards tribromide pyridine (pyridinium bromide perbromide) that 17-ketone group is changed at C 1617 of position halogenation, 17-ethylenedioxy derivative.By using potassium tert.-butoxide to carry out dehydrohalogenation in methyl-sulphoxide.Use tosic acid monohydrate in aqueous acetone solution, to carry out the deprotection of 17-ketone group.The reduction of 17-ketone group has produced 17-alcohol derivate.
One of shortcoming of method described in WO2004/041839 is to protect 3-OH functional group with benzyl, and described benzyl only can be removed by carrying out hydrogenation with Pd/C as catalyzer in the synthetic final step of oestetrol.In addition, the level of this catalyzer in final medicine must the determined and necessary ICH guide of observing.
Protection/the deprotection of two steps of synthetic another shortcoming Shi17-ketone group functional group described in WO2004/041839, thus the two keys of 15-16 produced.
Still need to improve 3-through protection-oxygen base-female-1,3,5 (10), 15-tetraene-17-alcohol synthetic.
Therefore, the object of this invention is to provide preparation 3-through protection-oxygen base-female-1,3,5 (10), the method for 15-tetraene-17-alcohol, described method has overcome at least one shortcoming of the prior art.
Summary of the invention
The current inventor has been found that can be by reaching this object by method defined in the appended claims.
According to a first aspect of the invention, provide preparation formula (I) compound (3-P 1-oxygen base-female-1,3,5 (10), 15-tetraene-17-alcohol) method:
Figure BDA0000424823160000021
Said method comprising the steps of:
A) formula (II) compound is reacted with production (III) compound, wherein P with acylating agent or silylating reagent 1and P 2independently of one another for being selected from R 1cO-or R 2-si-R 3r 4protecting group, R wherein 1for being selected from C 1-6alkyl or C 3-6the group of cycloalkyl, each group is optionally independently selected from fluorine or C 1-4one or more substituting group of alkyl replaces; R 2, R 3and R 4independently of one another for being selected from C 1-6the group of alkyl or phenyl, each group is optionally independently selected from fluorine or C 1-4one or more substituting group of alkyl replaces;
Figure BDA0000424823160000022
B) under the existence of acid chloride or derivatives thereof, make the reaction of described formula (III) compound, with production (IV) compound; And
Figure BDA0000424823160000031
C) described formula (IV) compound is reacted with production (I) compound with reductive agent.
Preferably, the method for preparation formula (I) compound has been contained in the present invention, said method comprising the steps of:
A) formula (II) compound is reacted with production (III) compound, wherein P with acylating agent or silylating reagent 1and P 2independently of one another for being selected from R 2-si-R 3r 4or R 1the protecting group of CO-, wherein R 1for being selected from C 1-6alkyl or C 3-6the group of cycloalkyl, each group is optionally independently selected from fluorine or C 1-4one or more substituting group of alkyl replaces; R 2, R 3and R 4independently of one another for being selected from C 1-6the group of alkyl or phenyl, each group is optionally independently selected from fluorine or C 1-4one or more substituting group of alkyl replaces;
B) in the presence of the acid chloride existing in the amount with catalytic amount or sub-chemical equivalent under oxygen atmosphere, make the reaction of described formula (III) compound with production (IV) compound; And
C) described formula (IV) compound is reacted with production (I) compound with reductive agent.
The invention provides the 3-P with synthetic significantly higher output known before comparable and/or lower cost presentation in next life (I) 1-oxygen base-female-1,3,5 (10), the improving one's methods of 15-tetraene-17-alcohol.
According to second aspect, the method for preparing oestetrol has also been contained in the present invention, and described method comprises by according to method preparation formula (I) compound of first aspect present invention, then makes formula (I) compound react to produce oestetrol.
According to the third aspect, the oestetrol by directly obtaining according to the method for second aspect present invention has also been contained in the present invention, and it is for being selected from following methods: the method for Hormone Replacement Therapy, the treatment method of vagina drying, the method for the method of contraception, hypersexuality, the method for processing skin, the method that promotes wound healing and treatment or prevention are selected from the method for the disease of autoimmune disease, breast tumor and colorectal carcinoma.
Above and other feature of the present invention, characteristic and advantage will become obviously by following detailed description, and this description illustrates principle of the present invention by example.
Detailed Description Of The Invention
Should also be understood that term used herein is not intended to restriction, because scope of the present invention is only limited by appended claims.
Unless context separately has clear indicating, otherwise the noun that does not have measure word to modify herein comprises one/kind of referent or more/kind.
Term used herein " comprise " and " by ... form " be synonym with " comprising " or " containing ", and be comprising property or open, do not get rid of member other, that do not give an example, key element or method steps.Should understand, term used herein " comprise " and " by ... form " comprise term " by ... form ".
Numerical range by endpoint reference comprises all numerals and part and the cited end points in the scope separately of being included into.
All reference of quoting in this specification sheets by reference integral body are incorporated to herein.The instruction of all reference of particularly, specifically mentioning is herein incorporated to by reference.
Unless otherwise defined, otherwise for disclose all terms of the present invention (comprising technical term and scientific terminology) have as one skilled in the art of the present invention the implication understood.By further guidance, comprise term definition to understand better instruction of the present invention.
In following paragraph, define in more detail different aspect of the present invention.The all respects that so limit can be combined with any other aspect, unless clearly illustrated that contrary with it.Especially, for preferred or favourable described any characteristic can be that preferred or favourable any other characteristic is combined.
In whole specification sheets, " embodiment " mentioned or " embodiment " mean described particular characteristics, structure or the feature relevant with this embodiment and are contained at least one embodiment of the present invention.Therefore, in whole specification sheets, " in an embodiment " of many places or the appearance of " in embodiment " phrase may not all refer to same embodiment, but can all refer to same embodiment.In addition, in one or more embodiment, particular characteristics, structure or feature can combine in any suitable manner, from combination described in present disclosure, are obvious for a person skilled in the art.In addition, when some described herein embodiments comprise some characteristics but do not comprise other characteristics that comprise in other embodiments, the combination of the characteristic of different embodiments means within the scope of the invention, and form different embodiments, as the skilled artisan will appreciate.For example, in claims, can be used in combination any embodiment of asking for protection with any.
Term " alkyl " itself or refer to by the singly linked straight or branched stable hydrocarbon group for example, for example, with 1 to 6 carbon atom (1 to 5 carbon atom, 1 to 4 carbon atom, preferred 1 to 3 carbon atom) of carbon-to-carbon as another substituent part.When using lower timestamp after carbon atom herein, subscript refers to the carbonatoms that described group can comprise.Therefore, for example, C 1-6alkyl means an alkyl to six carbon atom.The example of alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, 2-methyl butyl, amyl group, isopentyl and isomer, hexyl and isomer thereof.
Term " C 3-6cycloalkyl " as the part of group or group, refer to the saturated cyclic alkyls that comprises approximately 3 to approximately 6 carbon atoms.Monocycle C 3-6the example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Term " C 2-6thiazolinyl " itself or as another substituent part, refer to it can is the unsaturated alkyl that comprises one or more carbon-to-carbon double bond of straight or branched.C 2-6the example of thiazolinyl is vinyl, 2-propenyl, crotyl, 3-butenyl, pentenyl and isomer thereof, 2-hexenyl and isomer, 2 thereof, 4-pentadienyl etc.
Term " C 6-10aryl " itself or as another substituent part, refer to there is monocycle (being phenyl) or condense (for example naphthyl) together or the how unsaturated aryl radical of covalently bound a plurality of aromatic nucleus; it comprises 6 to 10 carbon atoms conventionally, and wherein at least one ring is aromatic nucleus.C 6-10aryl is also intended to comprise the partially hydrogenated derivative of cited carbocyclic ring system herein.C 6-10the limiting examples of aryl comprises phenyl, naphthyl, indanyl or 1,2,3,4-tetralyl.
Term " C 6-10aryl C 1-6alkyl " itself or as another substituent part, refer to herein defined in C 1-6alkyl, one of them or more hydrogen atom are by one or more C defined in this paper 6-10aryl substitutes.The example of aralkyl comprises benzyl, styroyl, dibenzyl methyl, aminomethyl phenyl methyl, 3-(2-naphthyl)-butyl etc.
Term " C 1-6alkyl-carbonyl " as a part of expression-CO-R of group or group agroup, R wherein afor the C defined in this paper 1-6alkyl.
Term " C 3-6naphthene base carbonyl " as the part of group or group, expression-CO-R cgroup, R wherein afor the C defined in this paper 3-6cycloalkyl.
Term " C 1-6alkanoic acid C 2-6alkene ester " refer to there is formula R b-O-CO-R acompound, R wherein afor the C defined in this paper 1-6alkyl and R bfor the C defined in this paper 2-6thiazolinyl.
Term " C 3-6naphthenic acid C 2-6alkene ester " refer to there is formula R b-O-CO-R ccompound, R wherein cfor the C defined in this paper 3-6cycloalkyl and R bfor the C defined in this paper 2-6thiazolinyl.
Term " carbonic acid C 1-6alkylene ester " refer to there is formula R b-O-CO-O-R acompound, R wherein afor the C defined in this paper 1-6alkyl and R bfor the C defined in this paper 2-6thiazolinyl.
The present invention relates to the 3-P of preparation formula (I) 1-oxygen base-female-1,3,5 (10), the method for 15-tetraene-17-alcohol, wherein P 1for being selected from R 1cO-, R 2si-R 3r 4protecting group; Wherein
R 1for being selected from C 1-6alkyl or C 3-6the group of cycloalkyl, each group is optionally independently selected from fluorine or C 1-41,2 or 3 substituting group of alkyl replaces; R preferably 1be selected from the group that comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each group is optionally independently selected from fluorine or C 1-41,2 or 3 substituting group of alkyl replaces; R more preferably 1for methyl, ethyl, propyl group, sec.-propyl, cyclopentyl or cyclohexyl, R more preferably also 1for methyl or ethyl;
R 2, R 3and R 4independently of one another for being selected from C 1-6the group of alkyl or phenyl, described C 1-6alkyl or phenyl is optionally independently selected from fluorine or C 1-61,2 or 3 substituting group of alkyl replaces; R preferably 2, R 3and R 4be selected from independently of one another the group that comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl and phenyl, each group is optionally selected from fluorine or C independently of one another 1-41,2 or 3 substituting group of alkyl replaces; R preferably 2, R 3and R 4be selected from independently of one another the group that comprises methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl and phenyl, each group is optionally selected from fluorine or C independently of one another 1-21,2 or 3 substituting group of alkyl replaces,
Figure BDA0000424823160000061
Said method comprising the steps of:
A) hydroxyl of protection (II) oestrone and ketone group are with production (III) compound, wherein P 1as above-mentioned restriction and P 2for being selected from R 1cO-, R 2-si-R 3r4 'sprotecting group,
Figure BDA0000424823160000062
B) for example, at acid chloride or derivatives thereof (Palladous chloride or three (dibenzalacetone) two palladium (Pd 2(dba) 3)) existence under make formula (III) compound reaction with production (IV) compound, described reaction is preferably carried out under the existence of oxygen atmosphere; And
Figure BDA0000424823160000071
C) formula (IV) compound is reacted with production (I) compound with reductive agent;
And if desired, any protecting group of using in above-mentioned reaction ruptures simultaneously or in succession; And
While needing, by being applicable to the ordinary method of functional group's conversion, make formula (I) compound be subsequently converted to another compound,
While needing, thus obtained formula (I) compound is split into its steric isomer.
In one embodiment, P 1for R 1cO-; P preferably 1for being selected from C 1-4alkyl-carbonyl or C 4-6the group of naphthene base carbonyl, each group is optionally independently selected from fluorine or C 1-41,2 or 3 substituting group of alkyl replaces; P more preferably 1for being selected from C 1-2alkyl-carbonyl or C 5-6the group of naphthene base carbonyl, each group is optionally independently selected from fluorine or C 1-21,2 or 3 substituting group of alkyl replaces; P for example 1be selected from ethanoyl or cyclohexyl-carbonyl, preferably P 1for ethanoyl.
In one embodiment, P 2for R 1cO-; P preferably 2for being selected from C 1-4alkyl-carbonyl or C 4-6the group of naphthene base carbonyl, each group is optionally independently selected from fluorine or C 1-41,2 or 3 substituting group of alkyl replaces; P more preferably 2for being selected from C 1-2alkyl-carbonyl or C 5-6the group of naphthene base carbonyl, each group is optionally independently selected from fluorine or C 1-41,2 or 3 substituting group of alkyl replaces; P for example 2be selected from ethanoyl or cyclohexyl-carbonyl, preferably P 2for ethanoyl.
In one embodiment, P 1and P 2be R independently of one another 1cO-.
In one embodiment, P 1for R 2-si-R 3r 4.P preferably 1be selected from and comprise the tertiary butyl-dimethyl-silica-based, phenylbenzene-methyl-silica-based, dimethyl-phenyl-silica-based, trimethylammonium-silica-based, triethyl-silica-based and triisopropyl-silica-based group, each group is optionally independently selected from fluorine or C 1-4one or more substituting group of alkyl replaces; P more preferably 1for the tertiary butyl-dimethyl-silica-based.
In one embodiment, step (a) comprises the following steps: (a1) use the hydroxyl of silylating reagent protection (II) compound with production (IIa) compound, wherein P 1for R 2-si-R 3r 4; And
Figure BDA0000424823160000081
(a2) under the existence of acylating agent the ketone group of protection (IIa) compound with production (III) compound, wherein P 2for R 1cO-.
In one embodiment, P 2for R 2-si-R 3r 4; P preferably 2be selected from and comprise the tertiary butyl-dimethyl-silica-based, phenylbenzene-methyl-silica-based, dimethyl-phenyl-silica-based, trimethylammonium-silica-based, triethyl-silica-based and triisopropyl-silica-based group, each group is optionally independently selected from fluorine or C 1-4one or more substituting group of alkyl replaces, more preferably P 2for the tertiary butyl-dimethyl-silica-based.
In one embodiment, P 1and P 2be R independently of one another 2-si-R 3r 4.
In one embodiment, P 1for R 2-si-R 3r 4; And P 2for R 1cO-.Preferably, P 1be selected from and comprise the tertiary butyl-dimethyl-silica-based, phenylbenzene-methyl-silica-based, dimethyl-phenyl-silica-based, trimethylammonium-silica-based, triethyl-silica-based or triisopropyl-silica-based group, each group is optionally independently selected from fluorine or C 1-4one or more substituting group of alkyl replaces; P more preferably 1for the tertiary butyl-dimethyl-silica-based; And P preferably 2for being selected from C 1-6alkyl-carbonyl or C 3-6the group of naphthene base carbonyl, each group is optionally independently selected from fluorine or C 1-41,2 or 3 substituting group of alkyl replaces; P preferably 2for being selected from C 1-4alkyl-carbonyl or C 5-6the group of naphthene base carbonyl; Each group is optionally independently selected from fluorine or C 1-21,2 or 3 substituting group of alkyl replaces; P more preferably 2for C 1-2alkyl-carbonyl or C 5-6naphthene base carbonyl, for example P 2for ethanoyl or cyclohexyl-carbonyl, preferred ethanoyl.
In one embodiment, the optional self-contained C of silylating reagent 1-6alkyl chloride SiClx, trifluoromethanesulfonic acid C 1-6alkyl estersil, phenyl-chloride SiClx, trifluoromethanesulfonic acid phenyl estersil, C 1-6alkyl phenyl silicon chlorides, trifluoromethanesulfonic acid C 1-6the group of alkyl phenyl estersil, each group is optionally independently selected from fluorine or C 1-4one or more substituting group of alkyl replaces.
In one embodiment, from oestrone preparation formula (I) 3-P of formula (II) 1-female 1,3,5 (10), the method for 15-tetraene-17-alcohol can be carried out according to 3 steps shown in scheme 1.Formula (I) compound can further react to prepare oestetrol afterwards.
Scheme 1
According to scheme 1, the hydroxyl of formula (II) oestrone and ketone group are preferably all protected in a step, with production (III) compound.
In one embodiment, P wherein 1and P 2be R independently of one another 1cO-, oestrone and acylation reaction.Preferably, described acylating agent is C 1-6alkanoic acid C 2-6alkenyl esters or C 3-6naphthenic acid C 2-6alkenyl esters.Preferably, acylating agent is selected from and comprises propionic acid C 2-6alkenyl esters, butyric acid C 2-6alkenyl esters, valeric acid C 2-6alkenyl esters, caproic acid C 2-6alkenyl esters, cyclopropionate C 2-6alkenyl esters, ring butyric acid C 2-6alkenyl esters, chaulmoogric acid C 2-6alkenyl esters and cyclohexylenedinitrilotetraacetic acid C 2-6the group of alkenyl esters.More preferably, acylating agent is selected from the group that comprises methylvinyl acetate, the different propylene of propionic acid, the different propylene of butyric acid, the different propylene of isopropylformic acid, vinyl-acetic ester, propionate, hexahydrobenzoic acid third-2-alkene ester, Cyclopentane carboxylic acid vinyl acetate and cyclohexylenedinitrilotetraacetic acid vinyl acetate.More preferably, acylating agent is selected from the group that comprises methylvinyl acetate, the different propylene of propionic acid, the different propylene of butyric acid, the different propylene of isopropylformic acid, vinyl-acetic ester and propionate.
Can under sour existence, carry out acidylate, for example, under the existence of sulfuric acid or at C 6-10under the existence of aryl sulfonic acid (optionally being replaced by one or more chlorine substituent).Suitable sour limiting examples comprises tosic acid and sulfuric acid.
For example, the oestrone of formula (II) can react with methylvinyl acetate under the existence of sulfuric acid or tosic acid ,-1,3 female to produce, and 5 (10), 16-tetraene-3,17--bis---alcohol, 3,17-diacetate esters.Can be under refluxing, optionally for example, under inert atmosphere (nitrogen atmosphere), react.The product so obtaining can be used for next step or for example, is further purified as chromatography (, adopting suitable eluent as dichloromethane/hexane or ethyl acetate/hexane on silicon-dioxide) by technology known in the art.
In one embodiment, P wherein 1and P 2be R independently of one another 2-si-R 3r 4, the oestrone of formula (II) reacts with silylating reagent.The optional self-contained trifluoromethanesulfonic acid C of silylating reagent 1-6alkyl estersil, trifluoromethanesulfonic acid phenyl estersil, trifluoromethanesulfonic acid C 1-6alkyl phenyl estersil, C 1-6alkyl chloride SiClx, C 1-phenyl-chloride SiClx, C 1-6the group of alkyl phenyl silicon chlorides, each group is optionally independently selected from fluorine or C 1-4one or more substituting group of alkyl replaces.
The formation through the silica-based ether of protection oestrone is carried out in the reaction that for example can pass through, and described silylating reagent is trifluoromethanesulfonic acid tertiary butyl dimethyl estersil, trifluoromethanesulfonic acid diphenyl methyl estersil, trifluoromethanesulfonic acid 3,5-dimethylphenyl estersil, trifluoromethanesulfonic acid trimethylsilyl group, trifluoromethanesulfonic acid triethyl estersil or trifluoromethanesulfonic acid triisopropyl estersil for example.Can for example, under the existence of appropriate base (imidazoles, 2,6-5 picoline, trimethylpyridine, triethylamine or 1,8-diazabicyclo [5.4.0], 11-7-alkene (DBU)), react.Can at room temperature or under refluxing react.Can for example, under the existence of suitable solvent (methylene dichloride, toluene or dimethyl formamide or its mixture), react.Also can for example, under the existence of appropriate base (LDA (LDA), tert-butyl lithium, two (trimethyl silicon based) acid amides sodium or potassium (NaHMDS, KHMDS) or tetramethyl piperidine lithium), for example, by the reaction of silylating reagent (t butyldimethylsilyl chloride, diphenyl methyl silicon chlorides, 3,5-dimethylphenyl silicon chlorides, trimethylammonium silicon chlorides, triethyl silicon chlorides or triisopropyl silicon chlorides), carry out the formation through the oestrone silicon ether of protection.
The step of present method (b) is included under the existence of acid chloride or derivatives thereof and makes the reaction of formula (III) compound with production (IV) compound, and described derivative is Palladous chloride or three (dibenzalacetone) two palladium (Pd for example 2(dba) 3), preferred acid chloride or Palladous chloride, more preferably acid chloride.
In one embodiment, described acid chloride or derivatives thereof can exist with chemical equivalent or sub-stoichiometric catalytic amount.
For example, step (b) can be preferably for example, be used acid chloride, Palladous chloride or three (dibenzalacetone) two palladiums of the amount of chemical equivalent, the acid chloride of the amount of preferred chemical equivalent carries out in suitable solvent (acetonitrile, cyanobenzene or methyl-sulphoxide, preferably cyanobenzene).
Can at room temperature carry out this reaction.
In another example, described step (b) can be at carbonic acid C 1-6for example, under the existence of alkylene ester (allyl carbonate) and under organo-tin compound exists as catalyzer, use sub-stoichiometric catalytic amount acid chloride, Palladous chloride or three (dibenzalacetone) two palladiums, preferably the acid chloride of sub-stoichiometric catalytic amount carries out.Preferably, organo-tin compound is tributyl methoxyl group tin.Preferably, carbonic acid C 1-6alkylene ester is methyl carbonic acid allyl ester.Reaction can be under reflux conditions, optionally for example, under inert atmosphere (nitrogen atmosphere or argon atmospher), carry out.
In another example, described step (b) can be used the acid chloride of sub-stoichiometric catalytic amount to carry out under oxygen atmosphere.In another example, described step (b) can be used the Palladous chloride of sub-stoichiometric catalytic amount to carry out under oxygen atmosphere.In another example, described step (b) can be used three (dibenzalacetone) two palladiums of sub-stoichiometric catalytic amount to carry out under oxygen atmosphere.
Preferably, described oxygen atmosphere is pure molecular oxygen or atmosphericoxygen (air or recirculated air, or renewable air).
Preferably, in step (b), the amount of acid chloride, Palladous chloride or three (dibenzalacetone) two palladiums is with respect to every equivalent formula (III) compound 0.50 equivalent, preferably 0.40 equivalent, more preferably 0.30 equivalent, also more preferably 0.2 equivalent, also more preferably 0.10 equivalent, also more preferably 0.05 equivalent, more preferably 0.03 equivalent at the most also at the most at the most at the most at the most at the most at the most.
In a preferred embodiment, step (b) under the existence of pure molecular oxygen or atmosphericoxygen, use with respect to every equivalent formula (III) compound at the most 0.10 equivalent acid chloride, preferably at the most the acid chloride of 0.05 equivalent, preferably the acid chloride of 0.03 equivalent carries out at the most.
Next step in method comprises with reductive agent reduction-type (IV) compound with production (I) compound.Preferably, described reductive agent is metal hydride compound.For example, the optional self-contained LiAlH of metal hydride compound 4, NaBH 4, NaBH (OAc) 3, ZnBH 4and NaBH 4/ CeCl 3group.Preferably, described reductive agent is NaBH 4/ CeCl 3.
For example, described reduction can (for example, in the mixture of tetrahydrofuran (THF) or methyl alcohol and tetrahydrofuran (THF)) be carried out in suitable solvent or its mixture.Reaction can be carried out at low temperatures, for example, lower than 15 ℃ (for example, lower than 10 ℃).
In one embodiment, formula (IV) compound is used described reductive agent to be directly reduced into alcohol without separation.In this embodiment, step (b) and (c) one pot (one pot) carry out.This one pot/two step process is that description is for the shortest chemical route of acquisition formula (I) compound.
Present method provides such advantage; the 17-hydroxy functional group of formula (I) compound also can be protected by protected base; described protecting group is acyl group for example; more preferably ethanoyl; its can be with 3-protecting group as 3-ethanoyl, preferably 3-acetoxyl group is removed simultaneously, described 3-protecting group provides 6 steps of the oestetrol of never describing synthetic.The 17-hydroxy functional group of formula (I) compound also can be by silica-based protection, described silica-based can being simultaneously removed with the silica-based protecting group of 3-, and the silica-based protecting group of described 3-provides 6 steps of the oestetrol of never describing synthetic.
According to another embodiment, step (a) can be carried out and comprise the following steps with two steps: (a1) use the hydroxyl of silylating reagent protection (II) compound with production (IIa) compound, wherein P 1for R 2-si-R 3r 4; And
(a2) under the existence of acylating agent, make the ketone group of formula (IIa) compound change into its enol ether with production (III) compound.
According to this embodiment, by oestrone preparation formula (I) 3-P of formula (II) 1-female 1,3,5 (10), the method for 15-tetraene-17-alcohol can be carried out as shown in scheme 2.
Scheme 2
In this embodiment of scheme 2 illustrated, P wherein 1be R independently 2-si-R 3r 4and P 2for CO-R 1, the oestrone of formula (II) reacts with silylating reagent with production (IIa) compound.The optional self-contained C of silylating reagent 1-6alkyl chloride SiClx, phenyl-chloride SiClx, C 1-6the group of alkyl phenyl silicon chlorides; Each group is optionally independently selected from fluorine or C 1-4one or more substituting group of alkyl replaces.
For example, the formation of the oestrone silicon ether through protecting can for example, be undertaken by the reaction of silylating reagent (t butyldimethylsilyl chloride, diphenyl methyl silicon chlorides, 3,5-dimethylphenyl silicon chlorides, trimethylammonium silicon chlorides, triethyl silicon chlorides or triisopropyl silicon chlorides).This reaction can for example, be carried out under the existence of alkali (imidazoles, 2,6-lutidine, trimethylpyridine, triethylamine or 1,8-diazabicyclo [5.4.0], 11-7-alkene (DBU)).
Next step is included in the ketone group of conversion type (IIa) compound under the existence of acylating agent with production (II) compound, wherein P 2for acyl group (formula (IIIa) compound).Suitable acylating agent and condition are as described above.
Next step in the method for scheme 2 is included in acid chloride or its derivative (Palladous chloride or three (dibenzalacetone) two palladium (Pd for example 2(dba) 3)) existence under make formula (IIIa) compound reaction with production (IV) compound, wherein P 1for R 2-si-R 3r 4(formula (IVa) compound).This reaction can be carried out as described above.
Next step in the method comprises with reductive agent reduction-type (IVa) compound with production (I) compound, wherein P 1for R 2-si-R 3r 4(formula (Ia) compound).This reaction can be carried out as described above.
The method according to this invention has advantages of such, can when end of synthesis, by ordinary method original position, remove protecting group, and described ordinary method for example uses fluorion (as tetra-n-butyl Neutral ammonium fluoride) to remove silica-based protecting group; As at Coppola, G.M.Org Prep Proced, 2007,39 (2), described in 199-292, it is incorporated to herein by reference; Or chloro-5 with 2,3-bis-, 6-dicyano p-benzoquinone removes silica-based protecting group, as at Tanemura, K.J Chem Soc, Perkin Trans11992, (22), described in 2997-2998; It is incorporated to herein by reference.
Present method has advantages of such, with this area formerly method compare, can by oestrone, be obtained the 3-P of formula (I) with the number of steps reducing 1-oxygen base-female 1,3,5 (10), 15-tetraene-17-alcohol, obtains oestetrol afterwards, and this is more convenient synthetic for economy and industrialization.
The method of preparing oestetrol is also contained in the present invention, and described method comprises uses method preparation formula of the present invention (I) compound, then makes formula (I) compound react to produce oestetrol.
The purposes in pharmaceutical compositions by the direct oestetrol obtaining of the inventive method has also been contained in the present invention, and described pharmaceutical composition is preferably used for being selected from following method: the method for Hormone Replacement Therapy, the treatment method of vagina drying, the method for the method of contraception, hypersexuality, the method for processing skin are, the method for promotion wound healing and treatment or prevention are selected from the method for the disease of autoimmune disease, breast tumor and colorectal carcinoma.
By following embodiment, but the present invention is not illustrated and is limited.
Embodiment
Embodiment 1: according to embodiment of the present invention preparation formula (I) compound, wherein P 1for ethanoyl.
Step 1: female-1,3,5 (10), 16-tetraene-3,17-glycol, 3,17-diacetate esters
By 100g3-hydroxyl-female-1,3,5 (10)-triolefins-17-ketone (0.370 mole) is poured in 500ml methylvinyl acetate and 10g tosic acid.Mixture is refluxed.Continuous steaming distillates acetone and methylvinyl acetate until temperature reaches 98 ℃.Make afterwards mixture be cooled to 0 ℃, add K 2cO 3.
After 0 ℃ of next hour, filtering mixt, concentrates gained solution and adds Di Iso Propyl Ether.By filtering collecting precipitation thing dry.It is weighed as 111.5g (productive rate: 85%).
1hNMR (CDCl 3) δ 0.90 (s, 3H, the CH of C-18 place 3), 1.30-1.50 (m, 11H), 2.20 (s, 3H, CH 3acetic ester), 2.30 (s, 3H, CH 3acetic ester), 2.30-2.50 (m, 2H), 5.54 (broad peak s, 1H)), 6.80 (broad peak s, 1H, H4), 6.82 (dd, 1H, H2), 7.27 (d, 1H, H1) mp=148.3C
Step 2:3-acetoxyl group-female-1,3,5 (10), 15-tetraene-17-ketone
To female-1 of 115.5g (0.315 mole), 3,5 (10)-tetraene-3,17-glycol, 3,17, in the 1500ml acetonitrile solution of diacetate esters, add 30.4g (0.095 mole) three normal-butyl methoxyl group tin and 11.2g (0.05 mole) acid chloride (II) and 20ml methyl carbonic acid allyl ester.Mixture is refluxed 2 hours, be then cooled to room temperature, and filter by silicagel pad.Reactant dilute with water afterwards, and be extracted with ethyl acetate.Be concentrated into original volume 1/3rd after, add lentamente 1000ml Di Iso Propyl Ether.By filtering collecting precipitation thing, with Di Iso Propyl Ether washing, for next step without being further purified.
1hNMR (CDCl 3) δ 1.10 (s, 3H, the CH of C-18 place 3), 1.30-2.60 (m, 9H), 2.30 (s, 3H, CH 33-acetic ester), 2.90-3.00 (m, 2H), 6.00-6.15 (m, 1H, H15), 6.80 (broad peak s, 1H, H4), 6.85 (dd, 1H, H2), 7.29 (d, 1H, H1), 7.60 (d, 1H, H16), mp:177.7C
Step 3:3-acetoxyl group-female-1,3,5 (10), 15-tetraene-17-alcohol
Make the material dissolves of collecting in 300ml tetrahydrofuran (THF) (THF), then add the methanol solution (300ml) of seven hydration Cerium II Chlorides (123g, 0.33 mole).Make mixture be cooled to 0 ℃, and portion-wise addition sodium borohydride (17.8g, 0.47 mole, 1.5 equivalents), make temperature keep below 5 ℃.Add while finishing, mixture is stirred one hour, then by adding 2N HCl solution (100ml), carry out cancellation.Make partly original position evaporation of solution, and add water (4L).By filtering collecting precipitation thing dry.From the mixture of ethanol/Di Iso Propyl Ether after crystallization, separated 3-acetoxyl group-female-1,3,5 (10), 15-tetraene-17-alcohol, productive rate is 75%.
1hNMR (CDCl 3) δ 0.85 (s, 3H, the CH of C-18 place 3), 1.20-2.50 (m, 8H), 2.30 (s, 3H, CH 33-acetic ester), 2.80-3.05 (m, 2H), 4.40 (broad peak s, 1H, H17), 5.75 (broad peak s, 1H), 6.04 (broad peak s, 1H), 6.80 (broad peak s, 1H, H4), 6.84 (broad peak s, 1H, H2), 7.29 (d, 1H, H1), mp:120.7 ℃
Embodiment 2: according to embodiment of the present invention preparation formula (I) compound, wherein P 1for t-Butyldimethylsilyl.
Step 1:3,17-di-t-butyl dimethylsilyl bis-female-1,3,5 (10)-16-tetraene-17-alcohol
In the 400ml dichloromethane solution of oestrone (50g, 0.185 mole) and 2,6-lutidine (62g, 0.58 mole), dropwise add trifluoromethanesulfonic acid tertiary butyl dimethyl estersil (102.6g, 0.39 mole).At room temperature make solution stirring 6 hours.Add water (300ml), with the diluting soln washing organic layer of sodium carbonate.Dichloromethane solution is partly evaporated, and add ethyl acetate.Di Iso Propyl Ether is added into this solution.Mixture is stirred 2 hours at 0 ℃.By filtering collecting precipitation dry.Obtain 83g title compound (90% productive rate).
1hNMR (CDCl 3) δ 0.20 (s, 12H, (CH 3) 2-Si-), 0.90 (s, 3H, the CH of C-18 place 3), 0.95 (s, 9H, (CH 3) 3-C-Si-), 1.00 (s, 9H, (CH 3) 3-C-Si-), 1.20-2.40 (m, 11H), 2.75-2.95 (m, 2H), 4.48 (m, 1H, H16), 6.58 (broad peak s, 1H, H4), 6.62 (dd, 1H, H2), 7.12 (d, 1H, H1), mp:97.6 ℃
Step 2:3-tertiary butyl dimethyl Si base-female-1,3,5 (10)-15-tetraene-17-ketone
In oxygen atmosphere, to 83g (0.166 mole) 3,17-di-t-butyl dimethylsilyl bis-female-1,3, adds 3.8g (0.017 mole) Pd (OAc) in the 400ml acetonitrile solution of 5 (10)-16-tetraene-17-alcohol 2.Mixture is stirred 12 hours at 40 ℃, by Celite pad, filter afterwards.Add the diluting soln of sodium carbonate, and be extracted with ethyl acetate mixture.
After concentrated, add Di Iso Propyl Ether, mixture is stirred one hour at 0 ℃.By filtration collect product (54.7g, 86% productive rate) and for next step without being further purified.
1hNMR (CDCl 3) δ 0.20 (s, 6H, (CH 3) 2-Si-), 1.00 (s, 9H, (CH 3) 3-C-Si-), 1.13 (s, 3H, the CH of C-18 place 3), 1.20-2.70 (m, 11H), 2.80-3.00 (m, 2H), 6.10 (dd, 1H, H15), 6.58 (broad peak s, 1H, H4), 6.62 (dd, 1H, H2), 7.11 (d, 1H, H1), 7.63 (dd, 1H, H16), mp:165 ℃
Step 3:3-tertiary butyl dimethyl Si base-female-1,3,5 (10), 15-tetraene-17-alcohol
The material (54.7g, 0.143 mole) of collecting is dissolved in 300ml THF, adds the methanol solution (300ml) of seven hydration Cerium II Chlorides (53.3g, 0.143 mole).Make mixture be cooled to 0 ℃, portion-wise addition sodium borohydride (8.12g, 0.213 mole, 1.5 equivalents) also makes temperature keep below 9 ℃.Add while finishing, mixture is placed one hour, by adding 2N HCl solution (100ml), carry out cancellation afterwards.Make partly original position evaporation of solution, then add water (4L).By filtering collecting precipitation dry.From the mixture of ethanol/Di Iso Propyl Ether, after crystallization, by filtration, collect product dry.It is weighed as 46.6g (85% productive rate).
1hNMR (CDCl 3) δ 0.20 (s, 6H, (CH 3) 2-Si-), 0.89 (s, 3H, the CH of C-18 place 3), 1.00 (s, 9H, (CH 3) 3-C-Si-), 1.20-2.40 (m, 10H), 2.75-2.95 (m, 2H), 4.40 (broad peak s, 1H, H17), 5.65-5.75 (m, 1H), 5.95-6.10 (m, 1H), 6.57 (broad peak s, 1H, H4), (6.60 dd, 1H, H2), 7.13 (d, 1H, H1) mp:107.5 ℃
Embodiment 3: according to embodiment of the present invention preparation formula (I) compound, wherein P 1for t-Butyldimethylsilyl.
Step 1:3-tertiary butyl dimethyl Si base-female-1,3,5 (10)-triolefins-17-ketone
In the 400ml dichloromethane solution of oestrone (100g, 0.37 mole), add imidazoles (50.36g, 0.74 mole) and t butyldimethylsilyl chloride (61.3g, 0.41 mole).Solution is at room temperature stirred 24 hours.Add afterwards water (200ml).Organic layer is partly evaporated, and add Di Iso Propyl Ether.By filtration, collect formed white solid dry.It is weighed as 135.2g,
Productive rate 95%, mp172 ℃.
1hNMR (CDCl 3) δ 0.20 (s, 6H, (CH 3) 2-Si-), 0.90 (s, 3H, the CH of C-18 place 3), 1.00 (s, 9H, (CH 3) 3-C-Si-), 1.20-2.60 (m, 13H), 2.75-2.95 (m, 2H), 5.65-5.75 (m, 1H), 6.58 (broad peak s, 1H, H4), 6.63 (dd, 1H, H2), 7.12 (d, 1H, H1) mp:171.6 ℃
Step 2:3-tertiary butyl dimethyl Si base-female-1,3,5 (10)-16-tetraene-17-acetic ester
By 135g (0.351 mole) 3-tertiary butyl dimethyl Si base-female-1,3,5 (10)-triolefins-17-ketone is poured in 600ml methylvinyl acetate and 12g tosic acid.Mixture is refluxed.Continuous steaming distillates acetone and methylvinyl acetate until internal temperature reaches 98 ℃.Make afterwards mixture be cooled to 0 ℃, and add salt of wormwood.After 0 ℃ of next hour, filtering mixt.Gained solution is partly concentrated, and add Di Iso Propyl Ether.By filtering collecting precipitation thing, and crystallization from the mixture of ethyl acetate and heptane.By filtration, collect product dry.It is weighed as 119.5g (productive rate 80%).
Step 3:3-tertiary butyl dimethyl Si base-female-1,3,5 (10)-15-tetraene-17-ketone
To 119.5g (0.280 mole) 3-tertiary butyl dimethyl Si base-female-1, in the acetonitrile solution (1500ml) of 3,5 (10)-16-tetraene-17-acetic ester, add 27.2g (0.085 mole) tributyl methoxyl group tin, 11.2g (0.05 mole) acid chloride and 64ml (0.560 mole) methyl carbonic acid allyl ester.Mixture is refluxed 2 hours, be then cooled to room temperature and filter by silicagel pad.Mixture dilute with water is also extracted with ethyl acetate.Be concentrated into original volume 1/3rd after, add Di Iso Propyl Ether, and make solution at 0 ℃ cooling one hour.
By filtration, collect product.It is weighed as 91g (85% productive rate), for next step without being further purified.
1hNMR (CDCl 3) δ 0.20 (s, 6H, (CH 3) 2-Si-), 1.00 (s, 9H, (CH 3) 3-C-Si-), 1.13 (s, 3H, the CH of C-18 place 3), 1.20-2.70 (m, 11H), 2.80-3.00 (m, 2H), 6.10 (dd, 1H, H15), 6.58 (broad peak s, 1H, H4), 6.62 (dd, 1H, H2), 7.11 (d, 1H, H1), 7.63 (dd, 1H, H16), mp:165 ℃
Step 4:3-tertiary butyl dimethyl Si base-female-1,3,5 (10)-15-tetraene-17-alcohol
As described in step 3 in embodiment 2, carry out reduction step: make the material dissolves of collecting in THF, and add the methanol solution of seven hydration Cerium II Chlorides (1 equivalent).Make mixture be cooled to 0 ℃, portion-wise addition sodium borohydride (1.5 equivalent) also makes temperature keep below 9 ℃.Add while finishing, mixture is placed one hour, by adding 2N HCl solution, carry out cancellation afterwards.Make partly original position evaporation of solution, and add water.By filtering collecting precipitation dry.From the mixture of ethanol/Di Iso Propyl Ether, after crystallization, by filtration, collect product dry.
1hNMR (CDCl 3) δ 0.20 (s, 6H, (CH 3) 2-Si-), 0.89 (s, 3H, the CH of C-18 place 3), 1.00 (s, 9H, (CH 3) 3-C-Si-), 1.20-2.40 (m, 10H), 2.75-2.95 (m, 2H), 4.40 (broad peak s, 1H, H17), 5.65-5.75 (m, 1H), 5.95-6.10 (m, 1H), 6.57 (broad peak s, 1H, H4), (6.60 dd, 1H, H2), 7.13 (d, 1H, H1) mp:107.5 ℃
Embodiment 4:
Use the listed different reagent of table 1 and reaction conditions to repeat the step 2 of embodiment 1.Obtained 3-acetoxyl group-female-1,3,5 (10), 15-tetraene-17-ketone.Productive rate and transformation efficiency in table 1, have been provided.
Table 1
Figure BDA0000424823160000181
THF: tetrahydrofuran (THF); ACN: acetonitrile; RT: room temperature; DMSO: dimethyl sulfoxide (DMSO); ND: undetermined.
Embodiment 5
Use the listed different reagent of table 2 and reaction conditions to repeat the step 2 of embodiment 2.Obtained 3-tertiary butyl dimethyl Si base-female-1,3,5 (10)-15-tetraene-17-ketone.Table 2 has provided productive rate and transformation efficiency.
Table 2
Figure BDA0000424823160000191
THF: tetrahydrofuran (THF); ACN: acetonitrile; RT: room temperature; DMSO: dimethyl sulfoxide (DMSO); ND: undetermined.
Although should be understood that and certain preferred embodiments and/or material have been discussed to provide according to embodiment of the present invention, can carry out multiple modification or variation and not deviate from scope and spirit of the present invention.

Claims (15)

1. the method for preparation formula (I) compound,
Figure FDA0000424823150000011
Said method comprising the steps of:
A) formula (II) compound is reacted with production (III) compound, wherein P with acylating agent or silylating reagent 1and P 2independently of one another for being selected from R 2-si-R 3r 4or R 1the protecting group of CO-, wherein R 1for being selected from C 1-6alkyl or C 3-6the group of cycloalkyl, each group is optionally independently selected from fluorine or C 1-4one or more substituting group of alkyl replaces; R 2, R 3and R 4independently of one another for being selected from C 1-6the group of alkyl or phenyl, each group is optionally independently selected from fluorine or C 1-4one or more substituting group of alkyl replaces;
B) under the existence of acid chloride or derivatives thereof, make the reaction of described formula (III) compound with production (IV) compound; And
Figure FDA0000424823150000013
C) described formula (IV) compound is reacted with production (I) compound with reductive agent.
2. method according to claim 1, wherein P 1for R 1cO-.
3. method according to claim 1, wherein P 1for R 2-si-R 3r 4.
4. method according to claim 3, wherein P 2for R 2-si-R 3r 4.
5. P wherein according to the method in any one of claims 1 to 3, 2for R 1cO-.
6. method according to claim 5, wherein step (a) comprises the following steps: (a1) with the hydroxyl of silylating reagent protection (II) compound with production (IIa) compound, wherein P 1have as the identical meanings defined in claim 3; And
Figure FDA0000424823150000021
(a2) under the existence of acylating agent the ketone group of protection (IIa) compound with production (III) compound.
7. according to the method described in any one in claims 1 to 3,5 and 6, wherein said acylating agent is C 1-6alkanoic acid C 2-6alkenyl esters or C 3-6naphthenic acid C 2-6alkenyl esters.
8. according to the method described in any one in claim 1,3 to 7, wherein said silylating reagent is selected from and comprises following group: C 1-6alkyl chloride SiClx, trifluoromethanesulfonic acid C 1-6alkyl estersil, phenyl-chloride SiClx, trifluoromethanesulfonic acid phenyl estersil, C 1-6alkyl phenyl silicon chlorides, trifluoromethanesulfonic acid C 1-6alkyl phenyl estersil, each group is optionally independently selected from fluorine or C 1-4one or more substituting group of alkyl replaces.
9. according to the method described in any one in claim 1 to 8, wherein step (b) is at carbonic acid C 1-6under the existence of alkylene ester and organo-tin compound, carry out.
10. according to the method described in any one in claim 1 to 9, wherein said acid chloride exists with stoichiometric amount.
11. according to the method described in any one in claim 1 to 9, and wherein said reaction is carried out in the presence of the acid chloride of the amount with catalytic amount or sub-chemical equivalent, and preferably described reaction is carried out under oxygen atmosphere.
12. according to the method described in any one in claim 1 to 11, and wherein the described reductive agent in step (c) is selected from metal hydride compound.
13. methods according to claim 12, wherein said metal hydride compound is selected from and comprises following group: NaBH 4/ CeCl 3, LiAlH 4, NaBH 4, NaBH (OAc) 3and ZnBH 4.
14. prepare the method for oestetrol, and described method comprises by according to method preparation formula (I) compound described in any one in claim 1 to 13, then makes formula (I) compound react to produce oestetrol.
15. oestetrols that directly obtain by claim 14, it is for being selected from following method: the method for Hormone Replacement Therapy, the treatment method of vagina drying, the method for the method of contraception, hypersexuality, the method for processing skin, the method that promotes wound healing and treatment or prevention are selected from the method for the disease of autoimmune disease, breast tumor and colorectal carcinoma.
CN201280026162.1A 2011-06-01 2012-06-01 Process for the production of estetrol intermediates Pending CN103703014A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710354709.5A CN107266514A (en) 2011-06-01 2012-06-01 Method for producing E4 intermediate

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201161492300P 2011-06-01 2011-06-01
EP11168561.6 2011-06-01
US61/492,300 2011-06-01
EP11168561 2011-06-01
PCT/EP2012/060447 WO2012164096A1 (en) 2011-06-01 2012-06-01 Process for the production of estetrol intermediates

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN201710354709.5A Division CN107266514A (en) 2011-06-01 2012-06-01 Method for producing E4 intermediate

Publications (1)

Publication Number Publication Date
CN103703014A true CN103703014A (en) 2014-04-02

Family

ID=45003353

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201280026162.1A Pending CN103703014A (en) 2011-06-01 2012-06-01 Process for the production of estetrol intermediates
CN201710354709.5A Pending CN107266514A (en) 2011-06-01 2012-06-01 Method for producing E4 intermediate

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201710354709.5A Pending CN107266514A (en) 2011-06-01 2012-06-01 Method for producing E4 intermediate

Country Status (24)

Country Link
US (1) US11053274B2 (en)
EP (1) EP2714710B1 (en)
JP (2) JP6425540B2 (en)
KR (1) KR101994805B1 (en)
CN (2) CN103703014A (en)
AU (1) AU2012264602B2 (en)
BR (1) BR112013030830B1 (en)
CA (1) CA2835981C (en)
CY (1) CY1118150T1 (en)
DK (1) DK2714710T3 (en)
EA (1) EA023991B1 (en)
ES (1) ES2579175T3 (en)
HR (1) HRP20160692T2 (en)
HU (1) HUE029252T2 (en)
ME (1) ME02454B (en)
MX (1) MX341561B (en)
PL (1) PL2714710T3 (en)
PT (1) PT2714710T (en)
RS (1) RS54880B1 (en)
SG (1) SG195118A1 (en)
SI (1) SI2714710T1 (en)
SM (1) SMT201600206B (en)
WO (1) WO2012164096A1 (en)
ZA (1) ZA201308446B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105837424A (en) * 2016-03-31 2016-08-10 常州大学 Synthetic method for 1-chloro-3-methyl-3-buten-2-one

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2835979C (en) 2011-06-01 2018-05-01 Estetra S.A. Process for the production of estetrol intermediates
PL2714710T3 (en) 2011-06-01 2017-03-31 Estetra S.P.R.L. Process for the production of estetrol intermediates
EP2383279A1 (en) 2011-07-19 2011-11-02 Pantarhei Bioscience B.V. Process for the preparation of estetrol
JP6196625B2 (en) 2011-10-07 2017-09-13 エステトラ エス．ペ．エール．エル． Method for producing estetrol
RS61777B1 (en) 2015-06-18 2021-06-30 Estetra Sprl Orodispersible tablet containing estetrol
ME03728B (en) 2015-06-18 2021-01-20 Estetra Sprl Orodispersible dosage unit containing an estetrol component
MY195019A (en) 2015-06-18 2023-01-03 Estetra Sprl Orodispersible dosage unit containing an estetrol component
SI3310345T1 (en) 2015-06-18 2021-05-31 Estetra Sprl Orodispersible tablet containing estetrol
KR20220144885A (en) 2016-08-05 2022-10-27 에스테트라, 소시에떼 아 레스폰서빌리떼 리미떼 Method for the management of dysmenorrhea and menstrual pain
JP6935766B2 (en) 2018-02-15 2021-09-15 日本精工株式会社 Spindle device
TWI801561B (en) 2018-04-19 2023-05-11 比利時商依思特拉私人有限責任公司 Compounds and their uses for alleviating menopause-associated symptoms
JOP20200260A1 (en) 2018-04-19 2019-10-19 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US20220348607A1 (en) 2019-09-27 2022-11-03 Industriale Chimica S.R.L. Process for preparing (15alpha,16alpha,17beta)-estra-1,3,5(10)-triene- 3,15,16,17-tetrol (estetrol) and intermediates of said process
IT201900021879A1 (en) 2019-11-22 2021-05-22 Ind Chimica Srl PROCESS FOR THE PREPARATION OF (15α, 16α, 17β) -ESTRA-1,3,5 (10) -TRIENE-3,15,16,17-TETROL (ESTETROLE) AND INTERMEDIATES OF THIS PROCESS
IT201900017414A1 (en) 2019-09-27 2021-03-27 Ind Chimica Srl Process for the preparation of (15α, 16α, 17β) -estra-1,3,5 (10) -trene-3,15,16,17-tetrol (Estetrol) and intermediates of said process
WO2023021026A1 (en) 2021-08-17 2023-02-23 Aspen Oss B.V. A synthetic pathway to estra-1,3,5(10)-triene-3,15a,16a,17b-tetrol
WO2023051937A1 (en) 2021-10-01 2023-04-06 Industriale Chimica S.R.L. Process for preparing (15alpha,16alpha,17 eta)-estra-1,3,5(10)-triene-3,15,16,17-tetrol (estetrol) monohydrate

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1735627A (en) * 2002-11-08 2006-02-15 潘塔希生物科学股份有限公司 Synthesis of estetrol via estrone derived steroids

Family Cites Families (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE144266C (en)
US3138588A (en) 1962-08-24 1964-06-23 American Home Prod 17-ketals of estrone and derivatives thereof
US3177206A (en) 1963-03-07 1965-04-06 American Home Prod Selective bromination of a-ring aromatic 17-ketalized steroids
US3433785A (en) 1966-07-11 1969-03-18 Sterling Drug Inc 15,16-disubstituted aromatic steroids,intermediates and processes
US3673180A (en) 1970-06-18 1972-06-27 Merck & Co Inc 19-nor-6,6-ethylene-20-spiroxenes
US4792620A (en) 1983-10-14 1988-12-20 Bp Chemicals Limited Carbonylation catalysts
US4739078A (en) 1984-02-17 1988-04-19 The Upjohn Company Use of borohydride-salt lanthanide salt reagents for stereo selective reduction of C-15-keto prostaglandin precursors
IE60780B1 (en) 1987-01-23 1994-08-10 Akzo Nv New 11-aryl steroid derivatives
DE3710728A1 (en) 1987-03-31 1988-10-13 Schering Ag METHOD FOR PRODUCING 17 (ALPHA) -ETHINYL-17SS-HYDROXY-18-METHYL-4.15-ESTRADIEN-3-ON AND THE NEW INTERMEDIATE PRODUCTS FOR THIS METHOD
US5073374A (en) 1988-11-30 1991-12-17 Schering Corporation Fast dissolving buccal tablet
US5340586A (en) 1991-04-12 1994-08-23 University Of Southern California Methods and formulations for use in treating oophorectomized women
JPH07101977A (en) 1993-10-05 1995-04-18 Kureha Chem Ind Co Ltd New estradiol derivative with reduced hormone action and growth factor inhibitor thereof
WO1997004752A1 (en) 1995-07-26 1997-02-13 Duramed Pharmaceuticals, Inc. Pharmaceutical compositions of conjugated estrogens and methods for their use
US6117446A (en) 1999-01-26 2000-09-12 Place; Virgil A. Drug dosage unit for buccal administration of steroidal active agents
TW548277B (en) 1999-07-16 2003-08-21 Akzo Nobel Nv Orally active androgens
US20020132801A1 (en) 2001-01-11 2002-09-19 Schering Aktiengesellschaft Drospirenone for hormone replacement therapy
PT1390040E (en) 2001-05-18 2007-04-30 Pantarhei Bioscience Bv Pharmaceutical composition for use in hormone replacement therapy
EP1260225A1 (en) 2001-05-18 2002-11-27 Pantarhei Bioscience B.V. A pharmaceutical composition for use in hormone replacement therapy
US7732430B2 (en) 2001-05-23 2010-06-08 Pantarhei Bioscience B.V. Drug delivery system comprising a tetrahydroxilated estrogen for use in hormonal contraception
ATE449606T1 (en) 2001-05-23 2009-12-15 Pantarhei Bioscience Bv TETRAHYDROXYLATED ESTROGEN CONTAINING DRUG DELIVERY SYSTEM FOR USE IN HORMONAL CONTRACEPTION
WO2003018026A1 (en) 2001-08-31 2003-03-06 Pantarhei Bioscience B.V. Use of estrogenic compounds in combination with progestogenic compounds in hormone-replacement therapy
WO2003041718A1 (en) 2001-11-15 2003-05-22 Pantarhei Bioscience B.V. Use of estrogenic compounds in combination with progestogenic compounds in hormone-replacement therapy
US6723348B2 (en) 2001-11-16 2004-04-20 Ethypharm Orodispersible tablets containing fexofenadine
HU227198B1 (en) 2001-11-27 2010-10-28 Richter Gedeon Nyrt Pharmaceutical composition for emergency contraception containing levonorgestrel
PL209558B1 (en) 2002-02-21 2011-09-30 Bayer Schering Pharma Ag Pharmaceutical compositions comprising one or more steroids one or more tetrahydrofolate components and vitamin b12
US20050147670A1 (en) 2002-05-29 2005-07-07 Impax Laboratories Inc. Oral disintegrating dosage forms
WO2003103684A1 (en) 2002-06-11 2003-12-18 Pantarhei Bioscience B.V. Method of treating or preventing immune mediated disorders and pharmaceutical formulation for use therein
EP1511498B1 (en) 2002-06-11 2012-11-21 Pantarhei Bioscience B.V. A method of treating human skin and a skin care composition for use in such a method
EP1526856B1 (en) 2002-07-12 2008-01-02 Pantarhei Bioscience B.V. Pharmaceutical composition comprising estetrol derivatives for use in cancer therapy
CA2503549C (en) 2002-10-23 2012-07-10 Pantarhei Bioscience B.V. Pharmaceutical compositions comprising estetrol derivatives for use in cancer therapy
DK1624878T3 (en) 2003-05-22 2007-01-08 Pantarhei Bioscience Bv Use of compositions comprising an estrogenic component for the treatment and prevention of musculoskeletal pain
CN102796160A (en) 2005-05-26 2012-11-28 索尔瓦药物有限公司 17ss-hsd1 and sts inhibitors
CN101228268A (en) 2005-07-25 2008-07-23 德累斯顿工业大学 Rna-dependent rna polymerase, methods and kits for the amplification and/or labelling of rna
US20070048369A1 (en) 2005-08-26 2007-03-01 National Starch And Chemical Investment Holding Corporation Mucosal delivery tablet
US20090221540A1 (en) 2006-01-09 2009-09-03 Pantarhei Bioscience B.V. Method of Treating An Acute Vascular Disorder
US20070286819A1 (en) 2006-06-08 2007-12-13 Warner Chilcott Company, Inc. Methods to administer ethinyl estradiol and prodrugs thereof with improved bioavailability
US20080113953A1 (en) 2006-06-08 2008-05-15 Warner Chilcott Company, Inc. Methods to administer solid dosage forms of ethinyl estradiol and prodrugs thereof with improved bioavailability
EP2029146B8 (en) 2006-06-08 2018-02-21 Allergan Pharmaceuticals International Limited Methods to administer solid dosage forms of ethinyl estradiol and prodrugs thereof with improved bioavailabilty
GB0621926D0 (en) 2006-11-03 2006-12-13 Medlock Medical Ltd Multi directional stretch tubular bandages
EP2086550A2 (en) 2006-11-29 2009-08-12 Wyeth Estrogen/ serm and estrogen/ progestin bi-layer tablets
JP5649305B2 (en) 2006-12-20 2015-01-07 テバ ウィメンズ ヘルス インコーポレイテッド Orally disintegrating solid dosage form containing progestin and method for producing and using the same
EP2114412B1 (en) 2007-01-08 2010-07-14 Pantarhei Bioscience B.V. Method of treating or preventing infertility in a female mammal and pharmaceutical kit for use in such method
TW200836773A (en) 2007-01-12 2008-09-16 Wyeth Corp Tablet-in-tablet compositions
EP2155205B1 (en) 2007-06-21 2011-12-21 Pantarhei Bioscience B.V. Treatment of meconium aspiration syndrome with estrogens
EP2170346B1 (en) 2007-07-19 2011-11-16 Pantarhei Bioscience B.V. Treatment or prevention of hypertensive disorders of pregnancy or fetal growth retardation
ES2403203T3 (en) 2007-08-31 2013-05-16 National University Corporation Nagoya University Method for producing carbonyl compound and prooxidant used for the production of carbonyl compound
EP2077272A1 (en) 2007-12-21 2009-07-08 Affibody AB Polypeptide libraries with a predetermined scaffold
EP2077273B1 (en) 2007-12-31 2011-09-14 Animal Technology Institute Taiwan Methods for separating casein from soluble proteins in a composition
US20110250274A1 (en) 2008-09-19 2011-10-13 Shaked Ze Ev Estriol formulations
DE102009007771B4 (en) 2009-02-05 2012-02-16 Bayer Schering Pharma Aktiengesellschaft Buccal administration system containing 17α-estradiol
CN102058604A (en) 2009-11-17 2011-05-18 北京万全阳光医学技术有限公司 Drug composition containing dienogest and estradiol valerate and preparation method thereof
US9603860B2 (en) 2010-07-28 2017-03-28 Laboratorios Leon Farma Sa Pharmaceutical compositions comprising active drugs, contraceptive kits comprising active drugs, and methods of administering the same
PL2714710T3 (en) 2011-06-01 2017-03-31 Estetra S.P.R.L. Process for the production of estetrol intermediates
CA2835979C (en) 2011-06-01 2018-05-01 Estetra S.A. Process for the production of estetrol intermediates
EP2383279A1 (en) * 2011-07-19 2011-11-02 Pantarhei Bioscience B.V. Process for the preparation of estetrol
WO2013012326A1 (en) 2011-07-19 2013-01-24 Pantarhei Bioscience B.V. Tablet containing dehydroepiandrosterone (dhea)
HUE033590T2 (en) 2011-08-11 2017-12-28 Estetra Sprl Use of estetrol as emergency contraceptive
WO2013037708A1 (en) 2011-09-16 2013-03-21 Ferring B.V. A fast dissolving pharmaceutical composition
JP6196625B2 (en) 2011-10-07 2017-09-13 エステトラ エス．ペ．エール．エル． Method for producing estetrol
US9808470B2 (en) 2012-04-19 2017-11-07 Universite De Liege Estrogenic components for use in the treatment of neurological disorders
EP2653163A1 (en) 2012-04-19 2013-10-23 Université de Liège Estrogenic components for use in the treatment of neurological disorders
WO2014159377A1 (en) 2013-03-14 2014-10-02 Teva Women's Health, Inc. Compositions containing tanaproget and natural estrogens
US9988417B2 (en) 2013-09-18 2018-06-05 Crystal Pharma, S.A.U. Process for the preparation of estetrol
MX369035B (en) 2013-12-12 2019-10-25 Donesta Bioscience B V Orally disintegrating solid dosage unit containing an estetrol component.
ME03728B (en) 2015-06-18 2021-01-20 Estetra Sprl Orodispersible dosage unit containing an estetrol component
RS61777B1 (en) 2015-06-18 2021-06-30 Estetra Sprl Orodispersible tablet containing estetrol
SI3310345T1 (en) 2015-06-18 2021-05-31 Estetra Sprl Orodispersible tablet containing estetrol
MY195019A (en) 2015-06-18 2023-01-03 Estetra Sprl Orodispersible dosage unit containing an estetrol component

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1735627A (en) * 2002-11-08 2006-02-15 潘塔希生物科学股份有限公司 Synthesis of estetrol via estrone derived steroids

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHI LIU等: "5-(Trimethylstannyl)-2H-pyran-2-one and 3-(Trimethylstannyl)-2H-pyran-2-one: New 2H-Pyran-2-one Synthons", 《J. ORG. CHEM.》, vol. 61, no. 19, 31 December 1996 (1996-12-31), pages 6693 - 6699, XP002665033, DOI: 10.1021/jo951394t *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105837424A (en) * 2016-03-31 2016-08-10 常州大学 Synthetic method for 1-chloro-3-methyl-3-buten-2-one

Also Published As

Publication number Publication date
BR112013030830A2 (en) 2016-08-30
HRP20160692T2 (en) 2016-09-23
CN107266514A (en) 2017-10-20
RS54880B1 (en) 2016-10-31
DK2714710T3 (en) 2016-06-27
KR101994805B1 (en) 2019-07-01
PL2714710T3 (en) 2017-03-31
JP6425540B2 (en) 2018-11-21
MX341561B (en) 2016-08-25
WO2012164096A1 (en) 2012-12-06
ME02454B (en) 2016-09-20
SMT201600206B (en) 2016-08-31
CY1118150T1 (en) 2017-06-28
BR112013030830B1 (en) 2019-12-03
EA201301316A1 (en) 2014-04-30
PT2714710T (en) 2016-07-12
KR20140036205A (en) 2014-03-25
EP2714710B1 (en) 2016-04-06
NZ617613A (en) 2015-12-24
JP2018024673A (en) 2018-02-15
SG195118A1 (en) 2013-12-30
US20140107358A1 (en) 2014-04-17
JP2014518199A (en) 2014-07-28
ES2579175T3 (en) 2016-08-05
JP6479912B2 (en) 2019-03-06
HRP20160692T1 (en) 2016-08-12
HUE029252T2 (en) 2017-02-28
US11053274B2 (en) 2021-07-06
CA2835981A1 (en) 2012-12-06
SI2714710T1 (en) 2016-08-31
EA023991B1 (en) 2016-08-31
EP2714710A1 (en) 2014-04-09
ZA201308446B (en) 2016-08-31
MX2013014045A (en) 2014-08-22
CA2835981C (en) 2018-07-24
AU2012264602B2 (en) 2017-03-09

Similar Documents

Publication Publication Date Title
CN103703014A (en) Process for the production of estetrol intermediates
CN103619867B (en) For generation of the method for oestetrol intermediate
AU2012264602A1 (en) Process for the production of estetrol intermediates
KR102007874B1 (en) Process for the production of estetrol
AU2011343615A1 (en) Methods and compounds for preparing 3alpha-oxygen substituted steroids
CN103781795A (en) Process for the preparation of estetrol
KR101362482B1 (en) Preparation of tetrabenazine and dihydrotetrabenazine
IL159814A (en) Process for the production of beraprost and its salts
JP6368351B2 (en) Method for the synthesis of difluorolactam analogues
PT1183250E (en) Semi-synthesis of paclitaxel using dialkyldichlorosilanes
CN111410607B (en) Process for preparing hexahydrofurofuranol derivative, intermediate and process for preparing the same
AU2002248764A1 (en) Synthesis of silyl camptothecins and silyl homocamptothecins
WO2002083694A1 (en) Synthesis of silyl camptothecins and silyl homocamptothecins
WO2018108130A1 (en) Process for preparation of novel androgen receptor antagonist
NZ617613B2 (en) Process for the production of estetrol intermediates
US20150119587A1 (en) Process for the preparation of 2-substituted-2-(6-(substituted)-7-methylbenzo[d][1,3]dioxol-4-yl)acetic acid derivatives
JP2008239513A (en) New method for producing chafuroside based on efficient flavone construction
CA2932145A1 (en) A process for the production of 19-norpregn-4-en-3,20-dione-17.alpha.-ol (gestonorone) and intermediates therefor
CN1640880A (en) Lovastation derivative and its preparing method
CN103980106A (en) Monomethyl cyclobutenedione preparation method
NZ621973B2 (en) Process for the production of estetrol

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
CB02 Change of applicant information

Address after: liege

Applicant after: Estelle Private Limited Liability Company

Address before: Belgium - greth hollogne

Applicant before: ESTETRA S A

COR Change of bibliographic data
RJ01 Rejection of invention patent application after publication

Application publication date: 20140402

RJ01 Rejection of invention patent application after publication